Angiogenin (ANG) is an angiogenic ribonuclease that has been shown by our lab to promote cancer cell proliferation by stimulating growth and survival pathways. We recently identified ANG as a novel regulator of hematopoietic stem cell (HSC) quiescence, suggesting that ANG differentially regulates cell growth in primitive versus mature cells. Quiescence is a vital property of stem cells, and is critical to maintaining normal stem cell behavior during crucial normal developmental processes, including hematopoiesis. Despite its protective role against stem cell exhaustion and malignancy, little is known about the factors that regulate HSC quiescence. We have demonstrated significantly elevated expression of ANG in primitive HSC populations and shown ANG control of stem cell pool size, cell cycle status, apoptotic activity, blood lineage differentiation, colony number, and mobilization. We also demonstrated stem cell exhaustion in a serial bone marrow (BM) transplantation model, indicating loss of quiescence in the absence of ANG. Moreover, several clinical studies have identified ANG as a factor upregulated in various hematological malignancies, including chronic myelogenous leukemia (CML), and aged Ang-/- mice develop a myeloproliferative disorder. This proposal aims to understand the exact functional role and mechanistic action of ANG during normal and malignant hematopoiesis. Based on our initial studies, we hypothesize that ANG controls stem cell quiescence in both a cell-autonomous and a non-cell autonomous manner during normal hematopoiesis, and the homeostatic control of ANG is disrupted in the malignant state. In this study we will (1) establish the requirement of ANG for HSC activity in vitro and in vivo, (2) determine the mechanism by which ANG maintains HSC quiescence, and (3) investigate the role of ANG and its receptor in leukemogenesis. Given that ANG has been shown to regulate quiescence, at least in part, in a non-cell autonomous manner in BM, we propose to identify the physiologically-relevant cell-of-origin of ANG in the BM niche using conditional knockout models developed by our lab. We will also identify the receptor through which ANG promotes HSC quiescence non-cell autonomously, and demonstrate therapeutic potential of this axis in vitro and in vivo. Moreover, we will identify ANG as a novel regulator of ribosomal activity and protein synthesis in HSCs and leukemia, and identify novel downstream targets in regulating quiescence. Last, we will examine its function and mechanism using a BCR-ABL model of leukemogenesis. Our study will identify ANG as a novel factor that is simultaneously a conductor of the quiescent state in normal HSCs and a potent regulator of the leukemic state. Since the homeostatic balance of critical stem cell properties is necessary for maintained blood production and prevention of malignant transformation, the understanding of factors that uniquely regulate this balance, such as ANG, is necessary for the development of key therapeutics in a variety of BM disorders, hematological malignancies, and in regenerative medicine.